Viruses of Cats and Humans

"But
the Kitten, how she starts,
Crouches, stretches, paws, and darts!
First at one, and then its fellow,
Just as light and just as yellow.
There are many nownow one
Now they stop and there are none."

The
Kitten and the Falling Leaves by William Wordsworth,
1804.

The patient's symptoms and prognosis tell an all-too-familiar
tale. The patient became infected several years before and
suffered an acute illness before his immune system brought
the virus under control. Then he was fine and lived without
symptoms for several years, but during this time the virus
was quietly weakening his immune system.

Now he is not eating, losing weight, reeling from high fever,
terrible diarrhea, swollen lymph nodes, and suffering from
chronic opportunistic infections. The patient is in the final
throes of the terrible disease that has ravaged millions worldwideacquired
immune deficiency syndrome (AIDS).

And though the story may sound familiar, the patient may
not be. The patient in this imaginary case is a cat, suffering
from the feline form of AIDS. Like the human disease, which
is caused by the "lentivirus" human immunodeficiency virus
(HIV), feline AIDS is caused by a lentivirus known as feline
immunodeficiency virus (FIV).

That two such different species as humans and cats could
suffer such similar diseases is perhaps not so surprising
considering the similarity between the two viruses that cause
these diseases. And FIV and HIV are very similar.

If you were to take an electron micrograph of human cells
infected with HIV and cat cells infected with FIV and hold
these two images right next to each other, you would see in
both images small spiky virions with a visible pill-shaped
capsid inside. They are the same size.

"It is impossible to tell them apart," says Professor John
Elder, who has studied FIV since the mid-1980s at The Scripps
Research Institute (TSRI), where he is currently supported
by the hard work of Staff Scientist Aymeric deParseval and
Research Associates Ying-Chuan Lin, Udayan Chatterji, and
Sohela de Rozieres.

A Virus is Discovered and Isolated

It was in 1986, just a few years after the initial alarms
had been raised about HIV, that FIV was discovered in California.
In 1986, Niels Pedersen, who is currently director of the
Center for Companion Animal Health at the University of California,
Davis, and Janet Yamamoto, who is now a professor in the University
of Florida's College of Veterinary Medicine, co-discovered
FIV.

As the story goes, there was a kindly woman who took in
straysmany strayshousing them in her large kennels.
She noticed an odd thing. Several cats under her care became
sick and eventually died seemingly as a result of sleeping
in the same pen as one particular feral cat. So she contacted
Pedersen, who took samples and eventually isolated a virion,
which under the electron microscope looked like an RNA virus
belonging to the lentivirus family.

Shortly thereafter, Elder began to collaborate with the
Pedersen laboratory to work on the virus taken from that isolate
and from another isolate from a cat belonging to former TSRI
investigators Fred Hefron and Maggie So.

"They had a cat that came down with FIV, and we isolated
the virus from it," says Elder.

Elder had been working at TSRI since the mid-1970s, and
he was considered an expert in retroviruses like the newly
discovered FIV. In fact, Elder and his laboratory had been
working on retroviruses for 10 years by the time FIV was discovered
in 1986.

"It was a natural progression for us to take our molecular
tricks over there and try to find out what the structure of
that virus was," says Elder.

The tricks Elder and his laboratory employed were basically
those of molecular cloningthey were experts at isolating
and amplifying the DNA of the virus so that it and its proteins
could be studied. Basically, what this entailed was to extract
the DNA from infected blood lymphocytes, chop it up with enzymes,
insert the DNA pieces into phage (a virus that infects bacteria),
and then infect bacteria with the phage.

Bacteria can easily be grown, providing a convenient way
of amplifying the DNA. Elder and his laboratory then had only
to look for the right pieces of DNA by labeling them with
radioactive probes and separating them.

"We found one [piece] that contained what looked to be the
whole virus," says Elder.

Then they took that piece of DNA and used it to transfect
cells. They then observed those cells and found that they
were productively replicating the virus, which they then isolated
so that they could sequence it. Elder and his colleagues also
made expression systems with many of the viral proteins so
that they could be produced and purified for biochemical studies
and other research.

Two Very Similar Viruses

Building on this initial work, Elder and his colleagues
at TSRI and elsewhere have been able to characterize the genomic
organization of FIV and, significantly, to compare it to that
of its cousin HIV. FIV and HIV, it turned out, have a lot
in common, which makes FIV a good model for studying an HIV-type
infection.

The similarities between the two viruses go deeper than
morphology. FIV, as a disease, represents as serious an epidemic
for the wild and domestic cat populations in the world as
HIV does for the human populations of the world.

Both are members of the lenti (slow) virus family and they
contain many of the same characteristic genes and proteins.
FIV, much like its human cousin HIV, has an RNA genome of
around 10,000 bases that is packaged in a protein and lipid
capsid and coat. HIV and FIV both code for a number of structural
genes, which encapsulate the RNA and are produced by a gene
called gag. In an infected cell, the virus produces
a large Gag polyprotein that is later chopped up into its
constituent pieces by an important viral enzyme called the
protease.

The protease and a few other necessary enzymes are encoded
by a viral pol gene. And HIV and FIV also encode env
genes, which makes a glycoprotein that sticks up out of the
coat of the virion and helps the virus infect cells.

At the amino acid level, Elder estimates, about 40 to 45
percent of the residues in FIV proteins are identical to those
in HIV. "We found," says Elder, "[that the FIV and HIV sequences]
were quite related."

In fact, he adds, some of the proteins are so similar that
they have almost identical structures. Elder and his colleagues
hope that their discoveries and successes in their research
on FIV will shed light on the problem of HIV.

"One very big parallel [between the two]," says Eder, "is
that FIV uses the chemokine receptor CXCR4, like many strains
of HIV."

Much like HIV, FIV requires the interaction of its surface
glycoprotein molecules with CXCR4. And, also like HIV, FIV
requires another receptor to maximize binding to the chemokine
receptor. In HIV, the required receptor is called CD4. The
exact receptor needed by FIV is, at the moment, not known.